Cardiac failure is one leading cause of mortality, which not only manifests in midlife with the development of hypertrophy in response to a variety of pathophysiological stress signals, and vascular lesions, but as result of undetected genetic conditions. The parent grant focuses on the identification of nodal points of signaling pathways that mediate morphological changes in the mature heart during development of the hypertrophic response. This proposal will extend the parent grant by studying the role of paracrine signals, including members of the neuregulin (NRG) family, during cardiac development, which may also play a role in remodeling of the heart at later stages. Our hypothesis is that the NRG and cognate receptors, erbBs, play an essential role in cell and tissue interactions leading to coordinated cardiac growth and maturation. Supporting evidence includes murine studies demonstrating lack oft trabeculation of the ventricular wall in isolated knockouts of NRG-1, or either cognate receptors, erbB2 or erbB4. However, molecular mechanisms downstream of NRG signaling are poorly understood. Components of this signaling pathway are being defined. Two related NRG genes, NRG-1, and NRG-2, are expressed in reciprocal patterns within the endocardium. It is suggested that NRG-1 or NRG-2 could mediate distinct functions during development by differential activation of erbB receptors. Therefore, we will design experiments utilizing a combined approach of in vitro and novel in vivo murine based model systems to study the cardiac requirement of the NRG signal pathway during development. We propose, in this application, first to determine the role of NRG-1 and NRG-2 in a whole-mouse embryo culture system to study cardiac chamber growth and maturation and in isolated cardiac muscle cells in culture to dissect the subsequent downstream molecular events. Finally, we will initiate the study of the in vivo requirement of the erbB receptors in ventricular cardiomyocytes during the course of cardiac development by a novel approach to achieve conditional and tissue specific inactivation of the erbB4 receptor. The experimental strategy has been designed to first identify candidate signaling molecules in a well characterized cultured myocardial cell system, followed by a rigorous assessment of their role in an in vivo model systems. The parent program focus on pathways, which extend signaling from the membrane to the nucleus, including gp130 and RXRalpha receptor signaling in cardiac remodeling during development of the hypertrophic response. The goal of this proposal is to study the requirement of the neuregulin signaling pathway in cardiac remodeling during the course of development.